Antimycotic benzisothiazoline derivatives

ABSTRACT

THE WEAKLY BASIC PRODUCTS OBTAINED FROM THE REACTION OF AN N-SUBSTITUTED-3-HALOGENOBENZIOTHIAZOLIUM HALOGENIDE AND AMMONIA, AND THE SALTS OF THESE PRODUCTS WITH STRONG ACIDS, POSSES ANTIMYCOTIC PROPERTIES. THE SUBSTITUENTS ON THE NITROGEN ATOM OF THE 3-HALOGENOISOTHIAZOLIUM HALOGENIDE CAN BE ALKYL GROUP OF 1 TO 7 CARBON ATOMS, BENZYL, CYCLOHEXYL, METHYLCYCLOHEXYL, PHENYL OR PHENYL SUBSTITUTED BY HALOGEN, NITRO, LOWER ALKYL, NITRO, LOWER ALKYL, LOWER ALKOXY OR DI-(LOWER ALKYL) AMINO. A TYPICAL EMBODIMENT IS THE HYDROCHLORIDE SALT OF THE PRODUCT OBTAINED FROM 2-METHYL-3-CHHLOROBENZISOTHIAZOLIUM CHLORIDE AND AMMONIA, SAID HYDROCHLORIDE BEING COLORLESS PRISMS AND HAVING THE EMPIRICAL FORMULA C8H8NS.HCL WITH A MELTING POINT OF 220*C.

United States Patent 3,790,587 ANTIMYCOTIC BENZISOTHIAZOLINE DERIVATIVES Horst Boshagen, Haan, and Manfred Plempel, Wuppertal- Elberfeld, Germany, assignors to Bayer Aktiengesellschaft, Leverkusen, Germany No Drawing. Continuation-impart of applications Ser. No. 566,199, July 19, 1966, and Ser. No. 783,756, Dec. 13, 1968, both now abandoned. This application June 10, 1971, Ser. No. 151,929

Claims priority, application Germany, July 29, 1965, P 45 844.3 Int. Cl. C07d 91/12 US. Cl. 260304 15 Claims ABSTRACT OF THE DISCLOSURE The weakly basic products obtained from the reaction of an N-substituted-3-halogenobenziothiazolium halogenide and ammonia, and the salts of these products with strong acids, possess antimycotic properties. The substituents on the nitrogen atom of the 3-halogenoisothiazolium halogenide can be alkyl group of 1 to 7 carbon atoms, benzyl, cyclohexyl, methylcyclohexyl, phenyl or phenyl substituted by halogen, nitro, lower alkyl, nitro, lower alkyl, lower alkoxy or di-(lower alkyl) amino. A typical embodiment is the hydrochloride salt of the product obtained from 2-methyl-3-chlorobenzisothiazolium chloride and ammonia, said hydrochloride being colorless prisms and having the empirical formula C H NS.HCl with a melting point of 220 C.

CROSS-REFERENCE This is a continuation-in-part of Ser. No. 566,199, filed July 19, 1966, and Ser. No. 783,756, filed Dec. 13, 1968, both now abandoned, Ser. No. 783,756, itself being a continuation-in-part of Ser. No. 566,199.

DETAILED DESCRIPTION The present invention pertains to new antimycotic agents of reduced toxicity and improved skin compatibility.

In particular, the present invention pertains to the weakly basic products obtained upon the treatment of an N- substituted-3-halogenobenzisothiazolium halogenide of the formula:

where R is an alkyl group of 1 to 7 carbon atoms, chloroalkyl of l to 7 carbon atoms, benzyl, cyclohexyl, methylcyclohexyl, phenyl or phenyl substituted by halogen, nitro, lower alkyl, lower alkoxy or di(lower alkyl) amino, and

X is chloro or bromo, with ammonia.

The present invention also pertains to the salts of these weakly basic products with strong acids.

By the term lower alkyl is meant a branched or straight chain hydrocarbon groups of from 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, sec.- butyl and tert.butyl. The term lower alkoxy refers to a similar hydrocarbon group which is bound to the remainder of the molecule by an oxygen atom.

A preferred group of compounds are those wherein R is alkyl of 1 to 4 carbon atoms, S-chloroethyl, benzyl, cyclohexyl, methylcyclohexyl, phenyl or methylphenyl.

3,790,587 Patented Feb. 5, 1974 The reaction products, on a molar basis, include not only one mole of the novel products but also two moles of HX, the N-substituted 3 halogenobenzisothiazolium halogenide yielding two moles of halide ion and the ammonia yielding two moles of hydrogen ion.

The products are obtained by introducing an N-substituted 3-halogenobenzisothiazolium halogenide into an excess of ammonia. Generally, this introduction is performed at a temperature of from about 5 to 10 with the ammonia being in a solution of, for example, methanol. Thus for example, the product is formed by adding one molar equivalent of an N-substituted-3-halogenobenzisothiazolium halogenide to one liter of 5 M ammonia in methanol at from 5 to 10 C. The hydrogen chloride generated combines with excess ammonia and precipitates as ammonium chloride. The product can be readily obtained by concentration, either of the reaction mixture containing the free base or with prior conversion to a salt through treatment with a strong acid. The products and their salts, after suitable purification such as through crystallization, are colorless crystalline materials. Suitable strong acids include naphthalene disulfonic acid, nitric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and the like.

The N substituted-3-halogenobenzisothiazolium halogenides employed as starting materials are prepared from N-substituted dithiosalicylic acids and phosphorous pentahalid )=.s according to known methods (Chem. Ber. 99, 2566 On the basis of the information presently available, it is believed the structure of the weakly basic product obtained according to this procedure can be diagrammatically depicted as:

NHR;

The imino form IV can be isolated in solid form as its salt from such an equilibrium mixture by removing unchanged amino starting material, as by nitrosation in an acidic solution, and thereafter recovering the imino salt. When either form is placed in a fluid state however, the above equilibrium occurs. In aqueous media this equilibrium is in the range of 40:60 to 60:40 aminozimino. Use of other solvents such as dimethyl-sulfoxide results in an equilibrium of :10 aminozimino.

The compounds obtained upon the treatment of an N- substituted-3 halogenobenzisothiazolium halogenide and ammonia, and the salt thereof with strong acids, exhibit antimycotic properties and are useful in human and veterinary medicine. Thus these compounds demonstrate excellent inhibition against Trichophyton m'entagrophytes, Candida albicans, Penicillium commune, Aspergillus niger and Microsporium felineum. They can be administered in conventional topical pharmaceutical formulation-s such as sprays, powders, creams and ointments which are prepared by techniques known per se. Particularly useful compositions are those in solution form. Suitable solvents include polar solvents or mixtures thereof such as dimethylsulfoxide, dimethylformamide; aliphatic primary alcohols of up to 6 carbon atoms, glycols having up to 3 hydroxyl groups such as glycerine, ethylene glycol and EXAMPLE 1 110 g. (0.5 mole) of 2-methyl 3 chloro-benzisothiazolium chloride (finely powdered) are introduced portionwise at to C. into 500 ml. of a saturated solution of NH in methanol (2.5 moles) while stirring vigorously. Stirring is continued for another 5 minutes in order to complete the reaction, the precipitated ammonium chloride is then filtered olf with suction, and the filtrate is evaporated in vacuo. The resultant syrup is taken up in 150 ml. of 1:1 hydrochloric acid (0.75 mole). The initially clear solution solidifies to a solid pulp after a few minutes. After standing in an ice bath for some time (30 minutes), the hydrochloride which has crystallized out is filtered off with suction, washed with a little cold Water and dried. 55 g. of product as hydrochloride salt are obtained which, after crystallization from ethanol, appear as colorless prisms of melting point 220 C. (sublim.). The yield represents 55% of quantitative for 3-methylaminobenzisothiazoliumchloride.

EXAMPLE 2 In a similar fashion to that described in Example 1, colorless, Well defined leafy prisms of melting point 171 C. (sublim.), corresponding to 3 ethylaminobenzisothiazole hydrochloride, are obtained from 2-ethyl-3-chlorobenzisothiazolium chloride.

EXAMPLE 3 In a simlar fashion to that described in Example 1, colorless, compact, well defined prisms of the product, corresponding to 3 (,6 chloroethylamino) benzisothiazole hydrochloride, are obtained through utilization of 2 (e chloroethyl) 3 chlorobenzisothiazolium chloride and demonstrate a melting point of 152 C. after crystallization from methanol.

EXAMPLE 4 (fi-chloroethyl) 3 imino 1,2 benzisothiazoline hydrochloride melting point 165-166 C. (dec.).

EXAMPLE 5 By treating 2 propyl 3 chlorobenzisothiazolium chloride with ammonia according to the procedure of Example 1, the product, corresponding to 3-propylaminobenzisothiazole hydrochloride, having a melting point of 111 C. is obtained.

EXAMPLE 6 By treating 2 butyl 3 chlorobenzisothiazolium chloride with ammonia according to the procedure of Example 1, the product, corresponding to 3-butylaminobenzisothiazole hydrochloride, is obtained in the form of colorless, compact prisms after crystallization from acetonitrile which melt at 155157 C., crystallize and exhibit a second melting point at 212 C.

EXAMPLE 7 Upon treating 2 isobutyl 3 chlorobenzisothiazolium chloride with ammonia according to the procedure of Example 1, the product, corresponding to 3-isobutylamino benzisothiazole hydrochloride, is obtained in the form of large colorless plates after crystallization from methanol, which melts at 187 C., crystallizes and exhibits a second melting point at 216 C.

EXAMPLE 8 By treating 2-cyclohexyl 3 chloro-benzisothiazolium chloride with ammonia, a product, 3-cyclohexylaminobenzisothiazole hydrochloride, is obtained as colorless, compact prisms of melting point 166 C.

Similarly, by utiliziing 2-(4-methylcyclohexyl)-3-chlorobenzisothiazolium chloride, a product, 3-(4-methylcyclohexylamino) benzisothiazole hydrochloride, is obtained which after crystallization from ethoxyethanol is in the form of colorless crystals having a melting point of 160 C.

Similarly, by utilizing 2-(3-methylcyclohexyl) -3-chlorobenzisothiazolium chloride, a product, 3-(3-methylcyclohexylamino) benzisothiazole hydrochloride, is obtained after crystallization from ethanol as colorless small needles of melting point 197 C. I

Similarly, but utilizing 2-(Z-methycyclohexyl)-3-chlorobenzisothiazolium chloride, a product, 3-(2-methylcyclohexylamino)-benzisothiazole hydrochloride, is obtained as colorless prisms of melting point 210 C. after crystallization from dimethylsulfoxide.

EXAMPLE 9 By treating 2-benzyl-3-chloro-benzisothiazolium chioride with ammonia, a product, 3-benzylaminobenzisothiazole, is isolated in the form of the free base as colorless, compact prisms having a melting point of C. after crystallization from methanol.

EXAMPLE 10 By treating 2-phenyl-3-chlorobenzisothiazolium chloride with ammonia according to the procedure of Example 1, a product, 3-phenylaminobenzisothiazole, is isolated in the form of the free base as colorless, bulbous crystals having melting point of 99 C. after crystallization from ethanol.

EXAMPLE 11 Upon treating 2-(4-methylphenyl)-3-chlorobenzisothiazolium chloride with ammonia according to the procedure of Example 1, a product, 3-(4-methylphenylamino)- benzisothiazole, is obtained as a free base as long yellowish needles of melting point 144 C. after crystallization from ethanol.

EXAMPLE 1?.

In addition, an equilibrium occurs between the salts of the 3-substituted'amiuobenzisothiazole, exemplified by Examples 1-3 and 5-10, and the salts of 3-amino-2-substituted benzisothiazoline salt, exemplified by Example 4, the proportions generally being in the range of 40:60 to 60:40, respectively. When dimethylsulfoxide is employed as the sole solvent, the ratio is generally :10 amino saltzimino salt. Such equilibrium mixtures, which demonstrate undiminished antimycotic activity, are typified by the following compositions, utilizing the product of Example 2 as its hydrochloride salt as the active ingredient whereby some of the corresponding 2-ethyl-3-amino- 1,2-benzisothiazoline hydrochloride is formed when the composition has stood at 20 C. for a period of days after preparation:

(A) A 1% solution for veterinary medical purposes from the product of Example 2 has been prepared as follows:

G. The hydrochloride of the product of Example 2 12.04 Dimethylsulfoxide 100.0

Isopropanol 100.0 Glycerine 300.0 Demineralized water, ad 1.000 1.

No'rn.l.=1iter=1000cc.

The ratio of the amino form to the imino form amounts to 40:60%, determined by high voltage paper electrophoresis.

(B) a 1% solution of:

The ratio of the amino form to the imino form amounts to 85 115%, determined by high voltage paper electrophoresis.

(C) A 10% solution for veterinary medical purposes:

The hydrochloride of the product of Example 2 120.4

Glycerine 500.0 Dimethylsulfoxide, ad 1.000 1.

The ratio of the amino form to the imino form amounts to 45:55%, determined by high voltage paper electrophoresis.

In the following the letters T, Ar, Eu and Em have the following meaning:

(D) A 1% ointment consisting of:

G. The hydrochloride of the product of Example 2 12.04 T 60 30.0 Ar 60 20.0 Eu G 100.0 Em MD 200.0

Dimethylsulfoxide Demineralized water, ad, 1000.0.

The ratio of the amino form to the imino form amounts to 55:45%, determined by high voltage paper electrophoresis.

6 (E) A 1% ointment consisting of:

G. The hydrochloride of the product of Example 2 12.04

T 60 30.0 Ar 60 20.0 Eu G 100.0 Em MD 150.0

Demineralized water, ad, 1000.0.

The ratio of the amino form to the imino form amounts to 50:50%, determined by ultra-violet spectroscopy.

(F) A 0.5% ointment consisting of:

Demineralized water, ad, 1000.0.

The ratio of the amino form to the imino form to 45 :55 determined by ultra-violet spectroscopy.

What is claimed is: 1. A compound selected from the group consisting of (a) a benzisothiazole of the formula:

wherein R is alkyl of from 1 to 7 carbon atoms, chloroalkyl of 1 to 7 carbon atoms, benzyl, cyclohexyl, methylcyclohexyl, phenyl or phenyl substituted by halogen, nitro, lower alkyl, lower alkoxy or di(lower alkyl) amino and (b) a salt thereof with a strong acid.

2. A compound according to claim 1 wherein R is alkyl of 1 to 4 carbon atoms, fi-chloroethyl, benzyl, cyclohexyl, methylcyclohexyl, phenyl or methylphenyl.

3. A compound according to claim 1 selected from the group consisting of 3-methylarninobenzisothiazole and the hydrochloride salt thereof.

4. A compound according to claim 1 selected from the group consisting of 3-ethylaminobenzisothiazole and the hydrochloride salt thereof.

5. A compound according to claim 1 selected from the group consisting of 3-propylaminobenzisothiazole and the hydrochloride salt thereof.

6. A compound according to claim 1 selected from the group consisting of 3-butylaminobenzisothiazole and the hydrochloride salt thereof.

7. A compound according to claim 1 selected from the group consisting of 3-isobutylaminobenzisothiazole and the hydrochloride salt thereof.

8. A compound according to claim 1 selected from the group consisting of 3-(fi-chlor0ethylamino)-benzisothiazole and the hydrochloride salt thereof.

9. A compound according to claim 1 selected from the group consisting of 3-cyclohexylaminobenzisothiazole and the hydrochloride salt thereof.

10. A compound according to claim 1 selected from the group consisting of 3-(4-methylcyclohexylamino)- benzisothiazole and the hydrochloride salt thereof.

11. A compound according to claim 1 selected from the group consisting of 3-(3-methylcyclohexylamino)-benzisothiazole and the hydrochloride salt thereof.

12. A compound according to claim 1 selected from References Cited the group consisting of 3-(2-methylcyclohexylamino)- benzisothiazole and the hydrochloride salt thereof. UNITED STATES PATENTS 13. A compound according to claim 1 selected from 3,187,001 6/1955 Meyer at 260-304 the group consisting of 3-benzylaminobenzisothiazole and 5 the hydrochloride salt thereof. QTHER REFERENCES 14. A compound according to claim 1 selected from Boshagen, Berlchte, 9 August 1966, pp. 2566-71. the group consisting of 3-phenylaminobenzisothiazo'le and the hydrochloride salt th f RICHARD J. GALLAGHER, Prlmary Examiner 15. A compound according to claim 1 selected from 10 the group consisting of 3-(4-methylphenylamino)-benzisothiazole and the hydrochloride salt thereof. 424-470 

